The first episode of schizophrenia may be the most critical period to examine mechanisms that influence treatment response and outcome of this chronically disabling disorder. Moreover, the examination of first episode patients provides a unique opportunity to study the biological basis of response without the potential confounds of prolonged antipsychotic drug exposure and other factors related to chronicity. The proposed Zucker Hillside Hospital (ZHH) CIDAR will integrate the extensive clinical experience of ZHH researchers focused on the treatment of first episode schizophrenia, with the expertise of investigators utilizing neurocognitive, neuroimaging, and molecular genetic approaches to identify biological predictors of treatment response and functional outcome. The proposed ZHH CIDAR will draw on a large number (n=242) of first episode schizophrenia patients to be enrolled in an NIMH-funded 12-week double-blind randomized clinical trial of risperidone versus aripiprazole (2R01 MH 60004). Funding of this CIDAR application will permit retention of these subjects for a full year of regular, reliable assessments of symptoms and side effects, in the context of a standardized, open-label treatment algorithm with risperidone and aripiprazole (or clozapine in treatment refractory patients) for the remainder of a total 52-week study period. Analyses will involve evaluating the ability of neurocognitive, neuroimaging, and molecular genetic variation to resolve the heterogeneity of short- and long-term response assessed comprehensively across a range of symptomatic, metabolic, neurocognitive and functional domains. Specifically, the ZHH CIDAR Operations and Clinical Assessment, Research Methods (cognitive neuroscience) and Special Scientific Procedures (genomics) cores will provide infrastructure for the following four projects: (1) Neurocognitive function and treatment response in first episode schizophrenia; (2) MR Imaging predictors of response and outcome in first episode schizophrenia; (3) Evaluation of striatal D2/D3 receptor availability in first episode schizophrenia; (4) Pharmacogenomics of treatment response in first episode schizophrenia. We believe the ZHH CIDAR represents a unique opportunity to dissect the heterogeneity of treatment response in a first episode cohort with minimal or no prior antipsychotic treatment and that the proposed work will lead to improved treatment as patients enter a critical phase of their illness. In addition, we expect that completing the proposed studies will facilitate the emergence of empirically-based strategies to individualize patient care and provide new data towards the development of the next generation of antipsychotic drugs.